| 1. |
- Galindo-Feria, Angeles S., et al.
(författare)
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Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies
- 2020
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Ingår i: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 72:1, s. 179-191
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Tidskriftsartikel (refereegranskat)abstract
- Objective Autoantibodies targeting histidyl-transfer RNA synthetase (HisRS; anti-Jo-1) are common in the idiopathic inflammatory myopathies (IIMs) and antisynthetase syndrome. This study was undertaken to investigate immunity against HisRS in the blood and lungs of patients with IIM/antisynthetase syndrome. Methods Bronchoalveolar lavage (BAL) fluid, BAL fluid cells, and peripheral blood mononuclear cells (PBMCs) from patients with IIM/antisynthetase syndrome (n = 24) were stimulated with full-length HisRS protein or a HisRS-derived peptide (HisRS(11-23)). BAL fluid and PBMCs from patients with sarcoidosis (n = 7) and healthy subjects (n = 12) were included as controls. The CD4+ T cell response was determined according to levels of CD40L up-regulation and cytokine expression using flow cytometry. Anti-Jo-1 autoantibody responses in the serum and BAL fluid were assessed by enzyme-linked immunosorbent assay. Lung biopsy samples from patients with IIM/antisynthetase syndrome (n = 14) were investigated by immunohistochemistry. Results In BAL fluid, CD4+ T cells from 3 of 4 patients with IIM/antisynthetase syndrome responded to stimulation with HisRS protein, as measured by the median fold change in CD40L expresssion in stimulated cells compared to unstimulated cells (median fold change 3.6, interquartile range [IQR] 2.7-14.7), and 2 of 3 patients with IIM/antisynthetase syndrome had the highest responses to HisRS(11-23) (median fold change 88, IQR 27-149)(.) In PBMCs, CD4+ T cells from 14 of 18 patients with IIM/antisynthetase syndrome responded to HisRS protein (median fold change 7.38, IQR 2.69-31.86; P < 0.001), whereas a HisRS(11-23) response was present in 11 of 14 patients with IIM/antisynthetase syndrome (median fold change 3.4, IQR 1.87-10.9; P < 0.001). In the control group, there was a HisRS(11-23) response in 3 of 7 patients with sarcoidosis (median fold change 2.09, IQR 1.45-3.29) and in 5 of 12 healthy controls (median fold change 2, IQR 1.89-2.42). CD4+ T cells from patients with IIM/antisynthetase syndrome displayed a pronounced Th1 phenotype in the BAL fluid when compared to the PBMCs (P < 0.001), producing high amounts of interferon-gamma and interleukin-2 following stimulation. Anti-Jo-1 autoantibodies were detected in BAL fluid and germinal center (GC)-like structures were seen in the lung biopsy samples from patients with IIM/antisynthetase syndrome. Conclusion The results of this study demonstrate a pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BAL fluid cells from patients with IIM/antisynthetase syndrome as compared to patients with sarcoidosis and healthy controls. These findings, combined with the presence of anti-Jo-1 autoantibodies in BAL fluid and GC-like structures in the lungs, suggest that immune activation against HisRS might take place within the lungs of patients with IIM/antisynthetase syndrome.
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| 2. |
- Bianchi, Matteo, et al.
(författare)
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Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
- 2022
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
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Tidskriftsartikel (refereegranskat)abstract
- Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
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| 3. |
- Chung, Yuen-Li, et al.
(författare)
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Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 57:4, s. 694-702
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To test the hypothesis that oral creatine supplements with exercise are more effective than exercise alone in improving muscle function in patients with established dermatomyositis or polymyositis receiving chronic medical therapies who are clinically weak yet stable. Methods. In a 6-month, 2-center, double-blind, randomized controlled trial, patients were randomized to receive oral creatine supplements (8 days, 20 gm/day then 3 gm/day) or placebo. All patients followed a home exercise program. The primary outcome was aggregate functional performance time (AFPT), reflecting the ability to undertake high-intensity exercise. Secondary outcomes included a Functional index measuring endurance and muscle bioenergetics on P-31 magnetic resonance spectroscopy (P-31 MRS). Patients were receiving stable immunosuppressive treatment and/or corticosteroids. Results. A total of 37 patients with polymyositis or dermatomyositis were randomized (19 to creatine, 18 to placebo); 29 completed 6 months. Intent-to-treat analyses demonstrated that AFPT improved significantly at 6 months with creatine (median decrease 13%, range -32-8%) compared with placebo (median decrease 3%, range -13-16%; P = 0.029 by Mann-Whitney U test). A completer analysis also showed significant benefits from creatine (P = 0.014). The functional index improved significantly with both creatine and placebo (P < 0.05 by paired Wilcoxon's rank sum test), with a significant benefit between groups in the completer analysis only. Phosphocreatine/beta-nucleoside triphosphate ratios using MRS increased significantly in the creatine group (P < 0.05) but not in the control group. No clinically relevant adverse events were associated with creatine. Conclusion. Oral creatine supplements combined with home exercises improve functional performance without significant adverse effects in patients with polymyositis or dermatomyositis. They appear safe, effective, and inexpensive.
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| 4. |
- Dastmalchi, Maryam
(författare)
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Studies of immunopathogenic mechanisms and treatment of chronic, inflammatory myopathies, myositis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Polymyosit (PM), dermatomyositis (DM) and sporadic inclusion body myositis (sIBM) are chronic inflammatory myopathies which are characterized by muscle weakness, fatigue and extra-muscular involvement. Mononuclear inflammatory cells are typically found in muscle tissue. Treatment is based on glucocorticoids together with other immunosuppressive agents. Despite favorable response most patients with PM and DM develop sustained muscle weakness and some patients do not respond at all, including sIBM. The explanation for this is unknown. Aims: The overall aim was to achieve increased understanding of disease mechanisms in myositis by evaluating therapeutic effects on muscle performance and variables in muscle tissue of pharmacological (high dose IVIg treatment and TNF-blockade, infliximab) and of non-pharmacological treatment, endurance and resistance training. Patients and methods: Clinical outcome measures (disease activity and muscle performance), laboratory tests and muscle biopsies were performed before and after the interventions. Muscle biopsies were investigated for signs of inflammation, fibrosis and muscle fiber characteristics. Patients with chronic, refractory myositis were treated with high dose IVIg for 12 weeks (study I, n= 13) or with infliximab for 16 weeks (study II, n= 12). In studies III and IV patients with chronic, stable and low active inflammatory DM or PM were applied to endurance training for 12 weeks (study III, n = 8) or resistance training for 7 weeks (study IV, n= 8). Results: After high dose IVIg treatment muscle performance improved in 3 of 13 patients. In two patients there were signs of decreased inflammation in muscle biopsies, but there was no correlation between improved muscle performance and changes of inflammatory markers in muscle tissue. There was still a pronounced expression of inflammatory markers in muscle tissue after treatment. After infliximab treatment 3 patients had decreased, 2 had increased and 5 had unchanged disease activity. Four stopped prematurely due to adverse events. Muscle performance did not improve in any patient. Signs of active inflammation by magnetic resonance imaging were apparent before treatment in two completers and after treatment in five cases. There were minor changes in inflammatory markers in muscle biopsies, but they were still present after treatment with infliximab in all patients. Before training a low proportion of oxidative, type I fibers (mean 32±10%) and an increased proportion of intermediate type IIC fibers (3± 3%) was apparent in muscle biopsies compared to in healthy individuals. After endurance training type I fibers had increased significantly (42±13%) and type IIC fibers were reduced to 1±1%. Improved muscle performance correlated to an increased proportion of type I fibers and increased type II fiber area. After resistance training improved muscle performance was associated with downregulation of several genes signalling for inflammation and fibrosis. Gene transcripts involved in metabolic regulation were also modified. Conclusion: Treatment with high dose IVIg or infliximab had limited clinical effects and there was no consistent decrease of inflammatory molecules expressed in muscle tissue. With infliximab treatment some patients even worsened, arguing against TNF as a key molecule in the underlying disease mechanism in chronic, treatment-resistant PM, DM and sIBM. In contrast, endurance as well as resistance training had positive effects on muscle performance and this was associated with changes in muscle characteristics and molecular expression in muscle, supporting the notion that non-immune mechanisms may have a role in causing muscle weakness.
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| 5. |
- Edelbring, Samuel, 1969-, et al.
(författare)
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Experiencing virtual patients in clinical learning : a phenomenological study
- 2011
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Ingår i: Advances in Health Sciences Education. - : Springer. - 1382-4996 .- 1573-1677. ; 16:3, s. 331-345
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Tidskriftsartikel (refereegranskat)abstract
- Computerised virtual patients (VPs) are increasingly being used in medical education. With more use of this technology, there is a need to increase the knowledge of students experiences with VPs. The aim of the study was to elicit the nature of virtual patients in a clinical setting, taking the students experience as a point of departure. Thirty-one students used VPs as a mandatory part of an early clinical rotation in rheumatology. Using the qualitative approach of phenomenology, we interviewed these students and then analysed data regarding their experiences of VPs as a learning activity. The result shows that students perceived VP activities in relation to actual patients, the clinical context and other learning activities. The VPs represented typical clinical cases which encouraged clinical reasoning and allowed for decision making. The students experienced the activities as integrating biomedical knowledge and clinical experience, providing structure that prepared for the unstructured clinical environment and patient encounters under unstressful conditions. However, the VPs were experienced as lacking the emotional interactivity and complexity of actual patients. Theoretical frameworks of clinical reasoning and experiential learning are suggested as foundations for further educational integration of VPs in the clinical environment. VP activities during clinical rotations provide experiences of clinical reality and allow students to solve problems actively. These features are dependent on VP technology but are also contingent on the surrounding environment.
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| 6. |
- Edelbring, Samuel, 1969-, et al.
(författare)
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Virtual Patients in clinical education from a phenomenological perspective
- 2009
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Konferensbidrag (refereegranskat)abstract
- Background: Although Virtual Patients (VPs) are more commonly used today there is no clear-cut picture of the nature of VPs as a learning tool. This means that educators hesitate in further curricular integration of VPs. Students and educators need examples of how this innovation can support student learning in practice.Summary of work: We have analysed the use of VPs in a clinical rotation of medical students of rheumatology lasting 2-4 weeks. The phenomenological approach was used in order to maximise the student perspective. Focus lied with the character of VP learning and the immediate framework supporting meaningful learning with VPs at the clinic. We interviewed31 students followed by a phenomenological analysis of the transcriptions. This resulted inincreased knowledge of the value of VPs in this setting.Summary of results: VPs as a learning tool play a role of enhancing the value of other learning activities at the clinic. The immediate framework affects the way that students approach VPs. When students work in pairs, reflection and argumentation strengthen the learning experience.Conclusions: The study approach provided a way to characterise learning with VPs as enhancing the value of clinical education.Take-home messages: Phenomenological research interviews provide a way of discovering the value of innovations in medical education.
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| 8. |
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| 9. |
- Lodin, Karin, et al.
(författare)
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Patient global assessment and inflammatory markers in patients with idiopathic inflammatory myopathies : A longitudinal study
- 2024
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Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier. - 0049-0172 .- 1532-866X. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- AimTo explore if patient global assessment (PGA) is associated with inflammation over time and if associations are explained by other measures of disease activity and function in patients with idiopathic inflammatory myopathies (IIM).MethodsPGA and systemic inflammatory markers prospectively collected over five years were retrieved from the International MyoNet registry for 1200 patients with IIM. Associations between PGA, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and creatine kinase (CK) were analyzed using mixed models. Mediation analysis was used to test if the association between PGA and inflammatory markers during the first year of observation could be explained by measures of disease activity and function.ResultsPGA improved, and inflammatory markers decreased during the first year of observation. In the mixed models, high levels of inflammatory markers were associated with worse PGA in both men and women across time points during five years of observation. In men, but not in women, the association between elevated ESR, CRP and poorer PGA was explained by measures of function and disease activity. With a few exceptions, the association between improved PGA and reduced inflammatory markers was partially mediated by improvements in all measures of function and disease activity.ConclusionIncreased levels of systemic inflammation are associated with poorer PGA in patients with IIM. In addition to known benefits of lowered inflammation, these findings emphasize the need to reduce systemic inflammation to improve subjective health in patients with IIM. Furthermore, the results demonstrate the importance of incorporating PGA as an outcome measure in clinical practice and clinical trials.
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| 10. |
- Munters, Li Alemo, et al.
(författare)
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Improved exercise performance and increased aerobic capacity after endurance training of patients with stable polymyositis and dermatomyositis
- 2013
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 15:4, s. R83-
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: This randomized, controlled study on patients with polymyositis or dermatomyositis was based on three hypotheses: patients display impaired endurance due to reduced aerobic capacity and muscle weakness, endurance training improves their exercise performance by increasing the aerobic capacity, and endurance training has general beneficial effects on their health status. Methods: In the first part of this study, we compared 23 patients with polymyositis or dermatomyositis with 12 age-and gender-matched healthy controls. A subgroup of patients were randomized to perform a 12-week endurance training program (exercise group, n = 9) or to a non-exercising control group (n = 6). We measured maximal oxygen uptake (VO2 max) and the associated power output during a progressive cycling test. Endurance was assessed as the cycling time to exhaustion at 65% of VO2 max. Lactate levels in the vastus lateralis muscle were measured with microdialysis. Mitochondrial function was assessed by measuring citrate synthase (CS) and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) activities in muscle biopsies. Clinical improvement was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) improvement criteria. All assessors were blinded to the type of intervention (that is, training or control). Results: Exercise performance and aerobic capacity were lower in patients than in healthy controls, whereas lactate levels at exhaustion were similar. Patients in the exercise group increased their cycling time, aerobic capacity and CS and beta-HAD activities, whereas lactate levels at exhaustion decreased. Six of nine patients in the exercise group met the IMACS improvement criteria. Patients in the control group did not show any consistent changes during the 12-week study. Conclusions: Polymyositis and dermatomyositis patients have impaired endurance, which could be improved by 12 weeks of endurance training. The clinical improvement corresponds to increases in aerobic capacity and muscle mitochondrial enzyme activities. The results emphasize the importance of endurance exercise in addition to immunosuppressive treatment of patients with polymyositis or dermatomyositis.
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